This SBIR Phase I proposal will set the groundwork for the clinical development of a first-in-class
treatment for the long-term management of chronic hyperactivity of the hypothalamic pituitary adrenal
axis (HPA) for alcohol use disorder (AUD). Therapeutics to modulate the HPA axis have been under
research for decades. While glucocorticoid receptor antagonists have shown some potential in the
treatment of AUD and depression, they can be counterproductive when used long-term. CRF receptor
type 1 (CRF1) antagonists have also been studied extensively but have generally been unsatisfactory
due to side effects and limited efficacy on the HPA. Thus, there is a considerable unmet medical need
for identification of novel therapeutics to normalize HPA hyperactivity that are effective and tolerable
for long-term use.
HPA hyperactivity is a key pathogenic driver of AUD and a validated therapeutic target. Excessive
activation of the HPA axis results in increased glucocorticoids release, which is associated with
harmful consequences on the central nervous system and peripheral organs. Prolonged exposure to
elevated glucocorticoids has detrimental actions on the central nervous system, causing hippocampal
and prefrontal cortex functional impairments, hyper-reactivity of neural and neuroendocrine
responses to stress. HPA feedback is disrupted in AUD due to overactivity. Evidence indicates that
preventing excessive HPA activation will restore HPA negative feedback and reset the system at
more physiological levels, reducing motivation for drinking and relapse.
While the stress response is essential for survival, it can become dysregulated, contributing to the
pathogenesis of a variety of illnesses, including AUD, and may result in detrimental interactions of
AUD and these conditions. This Phase I SBIR proposes the lead optimization and preclinical efficacy
testing of a novel candidate therapeutic aimed at the chronic management of pathologic HPA axis
hyperactivity for the treatment of AUD.